Kit for storage and mixing of agents of which at least one is liquid

ABSTRACT

A kit for mixing comprises a housing accommodating an ampoule containing a solid and a container containing a solvent which is either pre-pressurized or which may be pressurized when it is desired to mix to the liquid and solid components. A needle unit comprises a first needle, the opposite ends of which pierce rubber membranes closing the ampoule and the container, to establish a transport channel through which pressurized solvent flows from the container to the ampoule. The ampoule is vented through a second needle inserted through the membrane of the ampoule and provided with a micro-filter. In one embodiment, the needle unit is displaceable to cause the ends of the needles to pierce the respective membranes, and locked in place by a spring biased locking mechanism. A branch passage from the needle is connected to a cylinder containing a piston coupled to the locking mechanism. When the ampoule is full, pressure in the branch passage will rise, actuating the piston and releasing the locking mechanism. In an alternative embodiment, the needle mechanism is stationary, and the ampoule and container are moved into engagement with the respective needle ends.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a 35 U.S.C. 371 national application ofPCT/DK96/00085 filed Feb. 29, 1996 and claims priority under 35 U.S.C.119 of Danish application 0218/95 filed Mar. 2, 1995, the contents ofwhich are fully incorporated herein by reference.

BACKGROUND OF THE INVENTION

The invention relates to storage and mixing of agents of which at leastone is a liquid.

Many compositions which have a very short shelf life may be formed bymixing a pair of components which each has a long shelf life. Thecomponents may have the form of a powder and a liquid, respectively, andthe mixing may be obtained by dissolving the powder in the liquid, butalso the mixing of two liquids may lead to the provision of the wantedcomposition.

The wanted composition may be a solution or a suspension of a medicamentin a liquid where the composition resulting from the mixing is usablefor injection. E.g. solutions containing certain proteins have shown tobe very sensitive and it is therefore preferred to store the driedprotein isolated in a vial and to mix it with a solvent, which issimilarly isolated stored, a short time before the use of thecomposition. It shall be noticed that a composition also may be obtainedby mixing two liquids which are each stored in its own container as theyreact with each other in a way which results in a short shelf life forthe composition.

When the composition is a medicine for injection, the containers withthe isolated agents are commonly sold in a kit comprising a vialcontaining one agent, e. g. a protein, and a syringe or a cylinderampoule containing the liquid agent, e. g. the solvent for said protein.When the composition is going to be used, a needle mounted on thesyringe or the cylinder ampoule is passed with its pointed end throughthe closing rubber membrane of the vial, and the piston of the syringeor ampoule is pressed forward to press the solvent through the needleinto the vial to dissolve the agent in this vial. When the agent isdissolved and a liquid composition is provided, the piston is drawn backto suck up the solution into the syringe or the ampoule. The syringe maynow be used for the injection or the ampoule may be mounted in a syringeallowing the liquid composition in the ampoule to be divided intoseveral set doses, which may be injected at time intervals.

Even during the mixing the composition may show high sensitivity and themixing should take place without shaking the device and even adding ofthe solvent as a jet should be avoided. To obtain a gentle mixing thekit may comprise a plastic adaptor which may be mounted on the vial andwhich has means to guide the needle to an oblique position so that thesolvent hits the side wall of the vial rather than the freeze driedprotein itself.

Being dependant on the users skill and temper the mixing process is nota well defined process. If the users tactile motor function is reducedit may be a time consuming process to mount the adaptor on the vial,pierce the membrane of this vial, inject the solvent in the vial, waitfor the freeze dried product to be solved, and sucking the solution backinto the syringe, indeed it may be time consuming even for a skilledperson with a good tactile motor function. Further it depends on theusers temper how quickly the solvent is injected in the vial. It isrecommended to perform this injection sufficiently slowly so that thesolvent leaves the needle tip as drops rather than as a jet, as a jetmay have a whipping effect on the composition already formed and willincrease the formation of foam which is undesirable due to the fact thatthe foam has a high content of the solved agent which is then madeunavailable. The formation of foam further causes a higher risk for airbubbles in the solution sucked back into the syringe or the cylinderampoule and such air bubbles may have a deteriorating effect on thecomposition.

Another disadvantage by this known mixing kit is that the piston has tobe moved first forward to inject the solvent in the vial and thenbackward to suck the mixture back into the ampoule. By the forwardmovement of the piston a part of the inner wall of the cylinder ampouleis exposed to the ambient atmosphere and contaminating material maystick to this wall which is later on brought into contact with themixture which is sucked into the ampoule by pulling the piston backward.

BRIEF SUMMARY OF THE INVENTION

It is the object of the invention to provide a kit for storage andmixing of agents by which kit the above mentioned drawbacks are avoided.

This object is fulfilled by a kit for storage and mixing of componentswhereof at least one is liquid, which kit according to the invention ischaracterized in that it comprises a housing accommodating a containerwhich contains a solvent and is closed by a pierceable membrane, meansfor pressurizing the solvent in the container, a cylinder ampoule havinga first end closed by a pierceable membrane, and a needle unit withneedles which by an actuating movement of the needle unit in relation tothe housing may be forced to pierce the respective membranes, theneedles comprising a first needle with a first and a second pointed endfor piercing the ampoule closure membrane and the container closuremembrane, respectively, and a second needle having a pointed first endpiercing the ampoule membrane by the actuation movement and a second endopening to the atmosphere and being closed by a semipermeable membrane.

With this kit the housing may act as a storage package, and when anampoule with the mixture is going to be used, an actuator part of thekit is pressed to make the needles penetrate the membranes. Thereafterthe mixing takes place automatically as the solvent which is set underpressure will flow through the first needle from the container to theampoule which is vented through the second needle. Foam formed duringthe mixing will rise through the ampoule and the air in the foam bubbleswill escape through the venting second needle and through thesemipermeable membrane which lets only air and not liquid pass. Afterapproximately 30 seconds the ampoule is filled with liquid and as liquidcannot pass the semipermeable membrane, the supply of solvent to theampoule stops and the mixing is finished. When the mixing is finishedthe ampoule may be removed from the kit and used in a syringe. As theonly thing the user has to do is to press the actuator part and toremove the ampoule when the mixing is done, the user may consider thekit as an equivalent to a package with an ampoule with a ready mixedproduct. The user will not have to handle adaptors and needles and themixing is defined by the pressure in the container and the dimensions ofthe first needle and is not influenced by the user. Further only a minoramount of the active component is lost through the foam so that theoverall loss of active component is reduced to about 6-8% instead of theloss of about 16% which is known from the conventional vial/syringemixing procedure.

According to an embodiment of the kit according to the invention themeans for pressurizing the solvent in the container may be a springbiased piston forming the bottom of the container.

The means for pressurizing the solvent in the container may be designedto provide the pressurizing by the actuating movement. Thereby thesolvent may be stored in non-pressurized condition.

The container may be provided with a spring which is tightened when thekit is manufactured and which remains tightened during the storage ofthe container, or the spring may be tightened by the actuating movementas a first step of a mixing-sequence.

The first pointed end of the first needle and the second needle may becoaxial so that the second needle which has a larger diameter than thefirst needle surrounds the first end of the first needle.

The first needle may be provided with a throttling ensuring that theflow of the solvent from the container to the ampoule lasts for a presettime.

In an embodiment of the kit according to the invention the pressuringmeans may be damped so that the solvent takes a preset time to flow fromthe container to the ampoule.

Such a damping may be obtained e.g. by transmitting the pressurizingforce of the spring to the piston forming the bottom of the containerthrough a hydraulic transmission containing as viscous fluid the flow ofwhich may more precisely be throttled than the flow of the solventthrough the first needle.

The container and the ampoule may be positioned coaxially in the housingwith their closing membranes facing each other and the first needlelying between these closing membranes with its pointed first and secondend facing the respective membranes. By this embodiment the actuation isobtained by pressing the ampoule and the container towards each other.

Further in this embodiment a third needle may be mounted in the needleunit this third needle having a first pointed end piercing the membraneof the container by the actuation movement and a second end openingoutside the container and being closed by a semipermeable membrane, andthe container and the needle unit may fit sealingly against the innerwall of the housing. With this design a super atmospheric pressure isprovided between the needle unit and the container when this containerand the ampoule are pressed towards each other. By this superatmospheric pressure air will pass through the third needle into thecontainer to pressurize the solvent in this container. The length of thesecond pointed end of the needle must be adapted to the intendedposition of the container relative to the ampoule. If the ampoule isheld lower than the container this second pointed end shall just be longenough to pierce the membrane whereas it should reach to the bottom ofthe container if this container is placed beneath the ampoule during themixing unless the container is provided with a riser pipe bringing thesolvent to the top of the container when pressurised.

If the kit has to be positioned in a special way, e.g. standing on itsbottom side with the container placed above the ampoule, positionsensors may be provided which only allows the actuation movement to beperformed when the kit is placed in the right position.

The provision of at least one spring, which is tightened by theactuation movement so that this spring will draw out simultaneously thepointed needle ends from their membrane piercing positions when themixing is finished, will ensure that no solvent will spill when theampoule is removed.

In an embodiment of the kit according to the invention the first needlemay be provided with a branch tube connecting the opening of the needleto a space behind a piston in a cylinder. When the container containsmore liquid than necessary to fill the ampoule liquid will flow intosaid cylinder and force the piston outwards when the ampoule is full, asthe liquid cannot pass through the semipermeable membrane at the outerend of the ampoule venting needle. When the ampoule is full so that nomore liquid flows from the container to the ampoule the pressure in theneedle at the position of the branch tube will rise and liquid may bepressed into the cylinder and move the piston outwards. Via a piston rodthe outwards movement of the piston may be taken advantage of forperforming appropriate operations. E.g. the needles which are insertedthrough the closing membranes of the container and the ampoule against aspring force may be locked in this inserted position until the lockingis released by the influence of said piston rod. Thereby the needleswill be retracted from the container and the ampoule and the movement ofthe piston rod may further release a dispensing device which opens todispense the ampoule which now is filled with a protein solution andready for mounting into a pen syringe.

In an alternative embodiment of the kit according to the invention aninjection needle may be provided. This needle may communicate with theampoule, and to ensure that this communication is not established untilthe mixing has been performed, a three-way-valve may be providedconnecting the first needle and the first ampoule membrane penetratingend of this needle and the injection needle so that the first end ofsaid first needle may alternatively communicate with the rest of thisfirst needle and consequently with the container or with the injectionneedle. Switching of the valve may be performed by the movement of theabove mentioned piston rod when the mixing is finished.

When the valve is switched so that the ampoule communicates with theinjection needle, this injection needle may be inserted in a person andthe content of the ampoule may be injected either by pressing a pistonat the rear end of the ampoule into this ampoule or by releasing atightened spring which may press the piston into the ampoule.

BRIEF DESCRIPTION OF THE DRAWING

FIG. 1 schematically shows a first embodiment of a mixing kit accordingto the invention;

FIG. 2. shows a modification of the kit shown in FIG. 1;

FIG. 3 shows a second modification of the kit shown in FIG. 1;

FIG. 4 shows a third modification of the kit shown in FIG. 1; and

FIG. 5 shows schematically a second embodiment of the invention.

DETAILED DESCRIPTION OF THE INVENTION

An ampoule 1 with a content of a solid product 2 and a container 3 witha solvent 4 is accommodated in a housing 5. The ampoule 1 is of the kindwhich is at one end closed by a piston 6 an at the other has a neck 7which is terminated in a flange 8 against which a rubber membrane 9 isheld sealingly by a metal cap 10 which is beaded to grip behind theflange 8.

In the shown embodiment the container 3 is shaped like the ampoule 1 andis at one end closed by a piston 12 and at the other end by a rubbermembrane sealing against a flange terminating a neck. The solvent 4 ispressurized by a spring 11 which attempts to press the piston 12 intothe container.

The container may be shaped in other ways, e.g. as a small bottle with abottom forming an integral part of the bottle. Also pressurizing may beobtained in other ways, e.g. by a pressurized gas, and precautions maybe taken so that the solvent is not pressurized until the pressure shallbe used for driving the solvent out of the container.

A needle unit 13 is mounted on a guiding rail 14 projecting from thehousing 5 which rail allow movement of the needle unit 13 towards thehousing 5. A spring 15 keeps the needle unit at distance from thehousing. The needle unit 13 comprises a first needle 16 having a firstand a second pointed end 17 and 18, respectively, and the needle is sopositioned in the needle unit that its first and second ends willperforate the rubber membranes closing the ampoule 1 and the container3, respectively, when the needle unit is moved towards the housing alongthe guiding rail 14. The needle unit further comprises a second needle19 which has a pointed end, which is so positioned that it will piercethe rubber membrane of the ampoule 1 when the needle unit is movedtowards the housing 5 along the guiding rail 14, and another endterminated by a micro filter 20 which allows air but not bacteria topass.

When the needle unit 13 is moved towards the housing 5 the pointed ends17 and 18 of the first needle will pierce the membranes of the ampoule 1and the container 3, respectively. It is appropriate to make the firstpointed end 17 a little longer than the second pointed end 18 so as toensure that the first pointed end 17 communicates with the interior ofthe ampoule before the second pointed end 18 is connected to thepressurized solvent 4 in the container 3. After that communicationbetween the ampoule 1 and the container 3 is established through thefirst needle 16, the second needle may pierce the membrane of theampoule 1 to establish a vent for this ampoule.

The pressurized solvent in the container 3 will now be transmittedthrough the needle 16 to the ampoule 1 where it will solve the driedproduct 2. As the ampoule 1 is filled with liquid the air in thisampoule will escape through the vent formed by the needle 19 and themicro filter 20. The micro filter is so fine that contaminating bacteriacannot enter the ampoule through the filter. Further liquid cannotescape through the micro filter and consequently only the air but notthe liquid part of foam formed during the solving of the product canescape through the micro filter.

To avoid or to reduce the formation of foam when the solvent is led tothe product in the ampoule 1 it is appropriate to control the flow ofsolvent through the needle 16. This may be done by a throttling obtainedby using a very thin needle or by a partial compression of the walls ofthe needle. Another method is to control the pressurizing, e.g. byinserting a hydraulic system between the spring 11 and the piston 12 ofthe container. In the hydraulic system a medium may be used which ismore viscous than the solvent and the flow of which may consequently bemore easily controlled.

The needle 16 is provided with a branch tube 21 opening at the bottom ofa small cylinder behind a piston 22. As long as the solvent flowsthrough the needle 16 the pressure in said needle is low, but when theampoule is full and no liquid can pass out through the vent the flowthrough the needle 16 will stop and the pressure will rise to the levelof the pressure in the container 3. This pressure will work on the innerside of the piston 22 and try to force this piston out of the cylinder.In the schematically shown embodiment of the mixing kit advantage istaken of this fact. A construction ending in a locking pin 24 is mountedto the piston 22. A draw spring 23 is forcing the locking pin againstthe guiding rail 14 and the piston 22 into the cylinder. When the needleunit 13 against the force of the compression spring 15 is pressedtowards the housing 5 to make the pointed ends of the needles pierce therubber membranes of the ampoule 1 and the container 3, the locking pin24 will slide along the rail 14 until it reaches a recess 25. The spring23 will make the locking pin 24 engage this recess and the needle unit13 is locked in its position with its needles piercing the membranes ofthe ampoule and the container. The pressurized solvent will flow fromthe container 3 into the ampoule 1 and the air in this ampoule willescape through the needle 19 and the filter 20. When the ampoule is fulland all the air in this ampoule has escaped through the filter 20, thesolution in the ampoule will rise through the needle 19 but will bestopped by the filter 20. Then the flow through the needle 16 will stopand the pressure behind the piston 22 will rise and press this pistonoutwards in the cylinder against the force of the spring 23. Then thepin 24 will be drawn out of engagement with the recess 25 and the needleunit will be released and will by the spring 15 be pressed away from thehousing. Thereby the pointed needle ends will be drawn out of the rubbermembranes and the now filled ampoule may be taken out of the housing andused as a common ampoule filled with a liquid solution.

FIG. 2 shows a modification of FIG. 1 in which the pointed end 17 of thefirst needle 16 and the second, or venting, needle 19a are coaxial sothat the second needle 19a, which has a larger diameter than the firstneedle 16, surrounds the first end 17 of the first needle 16.

FIG. 3 shows a modification in which the first needle 16a is providedwith a throttling 32 such that the flow of solvent from the container tothe ampoule lasts for a preset time.

FIG. 4 shows another modification of FIG. 1 in which the flow of liquidfrom the container 3a to the ampoule 1 is damped. Such damping isobtained by transmitting the pressurizing force of the spring 11 to thepiston 12 forming the bottom of the liquid-containing chamber 4 througha hydraulic transmission containing a viscous fluid 30, the flow ofwhich of which is throttled. FIG. 3 shows a moveable piston 25, forcontaining the viscous fluid 30, on which the spring 11 acts. The flowof the viscous fluid in the chamber 30 toward the piston 12 may bethrottled in any suitable manner. FIG. 3 indicates a throttlingschematically using a disk 26 with a restrictive passage 27.

FIG. 5 shows an alternative embodiment in which the container 3b andampoule 1 are positioned coaxially in the housing 5a with their closingmembranes facing each other and the first needle 16a lying between theseclosing membranes with its pointed first 17 and second 18 ends facingthe respective membranes. In this embodiment, mixing is obtained bypressing the ampoule 1 and the container 3b towards each other. Asshown, a second, or venting, needle 19b, with a semipermeable membrane20a, is also provided to pierce the membrane of the ampoule 1 whenmixing the contents. The venting needle 19b is the same as the ventingneedle 19, i.e., contains a semipermeable membrane 20a located outsidethe housing 5a, except that, because the ampoule 1 and container 3b faceeach other, the needle is bent to extend sideways out of the housing 5a.

The needle unit 13a forms a partition in the housing 5a dividing thehousing 5a into a first and second compartment. The first needle 16a hasits first end 17 project into the first compartment and its second end18 project into the second compartment, the first and the second ends ofthe first needle facing the membranes of the ampoule 1 and container 3,respectively.

Also, in the FIG. 4 embodiment, a third needle 28 is mounted in theneedle unit 13a. The third needle 28 has a first pointed end piercingthe membrane of the container 3b by the actuation movement of thecontainer 3b and a second opening closed by a semipermeable membrane 28awhich will lie outside the container 3b when the end of the third needle28 pierces the container's membrane. As shown, the container 3b andneedle unit 13a fit sealing against the inner wall 29 of the housing 5a.Accordingly, when the container 3b and ampoule 1 are pressed towards oneanother, the space 31 between the container 3b and housing inner wall 29is pressurized to above atmospheric pressure, forcing air from the space31 through the needle 28 and into the container 3b to force out theliquid 4 through the needle 16a.

Practical embodiments may differ from this shown schematic embodiment indifferent ways without being beyond the scope of the invention. E.g. theguiding rail may be replaced by a number of pins at the corners of theneedle unit which pins are guided in bores in the housing. Part of theneedles and the cylinder may appear as channels or bores in a plasticblock which forms the needle unit. As mentioned the pressurizing of thesolvent is not necessarily provided by a spring but may be provided inother ways. Further a practical device may be provided with a dispensingmechanism which dispenses the ampoule when it is full so that the onlything a user has to do is to press the needle unit down towards thehousing and he will shortly thereafter receive a filled ampoule.

We claim:
 1. A kit for storage and mixing of components in which atleast one is liquid, comprising:a housing accommodating a containerwhich contains a solvent and is closed by a pierceable membrane, meansfor pressurizing the solvent in the container, and a cylinder ampoulehaving a first end closed by a pierceable membrane, and a needle unitwith needles which by an actuating movement, such actuating movementconstituting a relative movement between the needle unit and thecontainer and ampoule, pierce the respective membranes, the needlescomprising a first needle with a first and second pointed ends forpiercing the ampoule membrane and the container membrane, respectively,and a second needle having a pointed first end piercing the ampoulemembrane by the actuation movement and a second end opening to theatmosphere through a semipermeable membrane.
 2. A kit according to claim1, wherein the means for pressurizing the solvent in the container is aspring biased piston forming the bottom of the container.
 3. A kitaccording to claim 1, wherein the means for pressurizing the solvent inthe container is designed to provide the pressurizing in response to theactuating movement.
 4. A kit according to claim 3, wherein the firstpointed end of the first needle and the second needle are coaxial sothat the second needle which has a larger diameter than the first needlesurrounds this first end of the first needle.
 5. A kit according toclaim 1, wherein the first needle is provided with a throttling ensuringthat the flow of the solvent from the container to the ampoule lasts fora preset time.
 6. A kit according to claim 1, wherein the pressurizingmeans are damped so that the solvent takes a preset time to flow fromthe container to the ampoule.
 7. A kit according to claim 1, wherein thecontainer and the ampoule are positioned coaxially in the housing withtheir closing membranes facing each other, that the needle unit forms apartition in the housing dividing this housing into a first and a secondcompartment, and that the first needle has its first end projecting intothe first compartment and its second end projecting into the secondcompartment, the first and the second ends of the first needle facingthe membranes of the ampoule and the container, respectively.
 8. A kitaccording to claim 7, wherein a third needle is mounted in the needleunit, this, third needle having a first pointed end piercing themembrane of the container by the actuation movement and a second endopening outside the container and being closed by a semipermeablemembrane, and that the container and the needle unit fit sealinglyagainst the inner wall of the housing.
 9. A kit according to claim 1,wherein a spring is provided between the needle unit and the housing sothat this spring is tightened when the pointed ends of the first needleare passed through the ampoule and container closing membranes,respectively.
 10. A kit according to claim 9, wherein the first needleis provided with a branch tube connecting the bore of the needle to aspace behind a piston in a cylinder.
 11. A kit according to claim 10,wherein a locking mechanism (24, 25) is provided which by the actuatingmovement of the needle unit locks the housing and the needle unit in aposition with the needles penetrating the membranes, and that aconnection is provided from the piston in the cylinder to the lockingmechanism to unlock the housing and the needle unit when a pressure isestablished behind the piston.